Our goal in this Project is the elucidation of the role of the recently described inhibition of hedghog signaling by vitamin D3 as a mechanism underlying latitudinal variation in cancer mortality. Such variation has been known for nearly 70 years, and a prime role for sunlight-produced vitamin D stores has been postulated to be the mechanistic connection for three decades. Nonetheless, definitive proof linking increased vitamin D stores and reduction in relative risk of cancer remains elusive. Basal cell carcinomas (BCCs) are an ideal tumor in which to study this connection since aberrant hedghog signaling is pivotal to their development and maintenance, there are epidemiologic findings consistent with a role of ultraviolet radiation not only in their genesis but also in their restraint, and formidable tools now are available for their study. We will integrate both laboratory mouse models and human samples to address this question. Specifically we (i) will compare the effects of topical vs. oral vitamin D3 on BCC carcinogenesis in Ptch1 mice in which Cyp27B1 can be conditionally deleted, thus building on our preliminary data indicating that hedghog inhibition by topical D3 inhibits experimental murine BCC carcinogensis (ii) will compare the relative proportions of BCCs that are resistant to vitamin D3 inhibtion in the North vs. in the South in expectation that the proportion of vitamin D3-resistant BCCs will be higher in patients exposed to more sunlight and (iii) will compare UV-induced vitamin D3 production in subjects who have had BCCs with such production in persons who have had skin squamous cell carcinomas. Overall we expect that these studies will provide data making a compelling case for the conducting of a formal human trial of the anti-basal cell carcinoma chemopreventive efficacy of topical vitamin D3 and will form the foundation and template for extending these studies into extra-cutaneous tumors such as those of the colon, for which evidence is good for both a latitudinal gradient and a pathophysiologic role for hedgehog signaling. This Study is particularly germane now because growing concern that Dermatologists' relentless recommendations for sun avoidance to prevent skin cancers may be increasing the relative risk of extracutaneous cancers and because of the gathering momentum to increase the recommended daily vitamin D intake for the enitire population in unproved hopes that oral vitamin D supplements will convert the cancer risk of Minnesotans to that of Arizonans. Thus there is urgent need for further investigation into the relation of vitamin D3 to cancer risk. PUBLIC HEALTH RELEVANCE: The current rush by many experts to recommend increasing doses of supplemental oral D3 for cancer chemoprevention for the population emphasizes the urgency of obtaining further data bearing on the likely efficacy, let alone safety, of such recommendations. We propose a focused series of mouse and human studies that will illuminate the mechanism of chemoprevention by vitamin D of the most common human cancer, basal cell carcinoma. Not only will this develop the information needed for an interventional trial of BCC chemoprevention but also of great importance, these studies will serve as a model to inform future studies of the influence of vitamin D on the risk of colon and other more deadly extracutaneous cancers.